PROJECT SUMMARY Coccidioidomycosis, known as Valley fever, is caused by the fungal pathogen (Coccidioides) endemic to the San Joaquin Valley in California, Arizona, northern Mexico and arid areas of South America. Incidence in California is on the rise, and there is evidence indicating that the disease can be found in non-endemic regions including Washington State. Population expansion, travel, detection and/or weather changes appear to be contributing to an expanding endemic region. The health impacts of Valley fever infection can range from superficial to lethal. For the 60% of people who are infected, but do not display symptoms of Valley fever, the impact of the disease is likely to be minimal. For the 40% of symptomatic patients, most will display symptoms similar to the flu and the condition will resolve without treatment. Nevertheless, these patients can experience significantly impaired health for a lengthy period of time. For 1% of the patients, Valley fever results in a severe or prolonged clinical illness with dramatic health impacts, including chronic pulmonary nodules or cavities, with the potential for misdiagnosis, and even death. Disease is often misdiagnosed as a bacterial infection, often resulting in several rounds of antibiotic treatments before a correct diagnosis. The health impacts of Valley fever infection thus vary dramatically, and little is known about the biological factors that influence the severity of symptoms and health complications experienced following infection. Although the details are still unclear, cellular immune responses have long been shown to be critical for effective immunity to Coccidioides infection. We recently determined that the inability to resolve Coccidioides infection may be a result of elevated regulatory T cell frequency and functional capacity, and that regulatory T cell frequency may predict patient disease outcome at diagnosis. We propose to: 1) define the phenotype and function of regulatory T cells in Coccidioides infected patients during early disease, and 2) to define a biomarker algorithm that can be used at diagnosis for calibrating treatment aggressiveness for those patients most likely to develop chronic cocciodiomycosis. The successful completion of this project will provide diagnostic tools to identify patients earlier in their disease course for more aggressive treatment and closer monitoring for relapse after treatment, and will better define the immune mechanisms underlying chronic cocciodiomycosis.